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Examining the impact of laboratory housing temperature on murine CD28 and the response to anti-PD-1

检查实验室外壳温度对小鼠 CD28 的影响以及抗 PD-1 的反应

基本信息

批准号：
10751424
负责人：
Caitlin M James
金额：
$ 3.25万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751424
关键词：
Address Affect Animal Housing Animal Model Animals Basal metabolic rate Biomedical Research CD28 gene CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Caring Chronic Clinic Clinical Data Development Down-Regulation Flow Cytometry Genetically Engineered Mouse Goals Guidelines Harvest House mice Housing Human Immune Immune checkpoint inhibitor Immunologics Immunotherapy Impairment In Vitro Institution Knockout Mice Knowledge Laboratories Laboratory Animal Science Laboratory Animals Malignant Neoplasms Measures Mediating Medical Modeling Molecular Molecular Target Mus Nerve Norepinephrine Outcome Pathway interactions Patients Phenotype Physiological Play Pre-Clinical Model Process Publishing Receptor Signaling Reproducibility Research Research Proposals Rodent Role Signal Induction Signal Transduction Standardization Surface Sympathetic Nervous System T-Cell Activation T-Lymphocyte Temperature Testing Thermogenesis Training Tumor Immunity Tumor-Infiltrating Lymphocytes Work adrenergic stress anti-PD-1 anti-tumor immune response anticancer research beta-adrenergic receptor cancer therapy career cold stress design effector T cell environmental stressor experience falls functional disability guide for the care and use of laboratory animals human disease human model improved in vivo insight mRNA Expression melanoma mouse model novel therapeutics pre-clinical preclinical study protein expression receptor response success therapy development translational potential treatment response tumor tumor growth tumor immunology

项目摘要

Project Abstract/Summary For decades, animals in biomedical research have yielded significant scientific and medical breakthroughs by generating the essential preclinical data that ultimately support the discovery and development of treatments for human diseases, including cancer. However, while we to rely on animal models to investigate the complexity of cancer and cancer therapies, these preclinical studies have alarmingly low success in reproducibility, and even lower preclinical-to-clinical success rates. As per the Guide for the Care and Use of Laboratory Animals 8th Edition, research institutions have standardized, minimum guidelines for the housing, husbandry, and overall care for laboratory animals that they must adhere to. A mildly cool ambient temperature is a critical aspect of animal housing that has been shown to elicit significant physiological changes to research rodents, driven by the activation of the sympathetic nervous system and increased β- adrenergic receptor (β-AR) signaling as a result of the systemic release of norepinephrine. This is due to the compensatory response, known as non-shivering thermogenesis, employed by rodents housed at temperatures that fall below their thermoneutral zone (which is the range of ambient temperatures at which heat generated by basal metabolism is sufficient for maintaining homeostatic core temperature. ) Our lab has previously established that standard (ST), subthermoneutral laboratory housing temperatures result in significant impairment to the murine CD8+ T cell-dependent anti-tumor immune response compared to mice house at thermoneutral temperatures (TT). Additionally, we have shown that the immune checkpoint inhibitor αPD-1, an immunotherapy that has recently seen success as a front-line approach to treating cancers like melanoma, has improved efficacy in treating tumor-bearing mice housed at TT in a β-AR-dependent manor. Although published and preliminary data indicate a role for the co-receptor, CD28, in the diminished anti-tumor function of CD8+ T cells as a result of increased β-AR signaling, a gap exists in our understanding of the mechanisms underlying the reduced CD8+ T cell activation and effector function in mice housed at ST. Therefore, we propose using genetically engineered mouse models to precisely interrogate CD28 signaling and test hypothesis that standard housing temperatures impairs CD8+ T cell anti-tumor immunity and the in vivo efficacy of αPD-1 via impaired CD28 co-stimulation. We will use in vitro and in vivo approaches to examine the effects of housing temperature on CD8+ T cell CD28 expression and signaling, as well as tumor- infiltrating lymphocytes in mice treated with αPD-1 therapy. The studies outline in this proposal have the potential to identify a previously undefined mechanism by which subthermoneutral laboratory animal housing temperatures influence experimental outcomes of cancer and immunotherapy models, while also characterizing a widely underappreciated variable that exists in our animal models.

项目摘要/总结